Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease
Alexis Hofherr, Elena Liarte Marin, Barbara Musiał, Asha Seth, Tim Slidel, James Conway, David Baker, Pernille Hansen, Benjamin Challis, Stefano Bartesaghi, Maria Bhat, Roberto Pecoits‐Filho, Tu Xiao, Viknesh Selvarajah, Kevin Woollard, Hiddo J.L. Heerspink
Abstract
BackgroundInflammation is a significant contributor to cardiorenal morbidity and mortality in diabetic kidney disease (DKD). The pathophysiological mechanisms linking systemic, sub-acute inflammation and local, kidney injury-initiated immune maladaptation is partially understood.MethodsHere, we explored the expression of pro-inflammatory cytokines in patients with DKD; investigated mouse models of type 1 diabetes (T1D) and type 2 diabetes (T2D); evaluated glomerular signaling in vitro; performed post hoc analyses of systemic and urinary markers of inflammation; and initiated a phase 2b clinical study (FRONTIER-1; NCT04170543).ResultsTranscriptomic profiling of kidney biopsies from patients with DKD revealed significant glomerular upregulation of IL-33. Inhibition of IL-33 signaling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model (T2D/DKD). On a cellular level, inhibiting IL-33 improved glomerular endothelial health by decreasing cellular inflammation and reducing release of pro-inflammatory cytokines. Therefore, FRONTIER-1 was designed to test the safety and efficacy of the IL-33-targeted monoclonal antibody tozorakimab in patients with DKD. So far, 578 patients are enrolled in FRONTIER-1. The baseline inflammation status of participants (N > 146) was assessed in blood and urine. Comparison to independent reference cohorts (N > 200) validated the distribution of urinary TNFR-1 and CCL2. Treatment with dapagliflozin for 6 weeks did not alter these biomarkers significantly. Complete FRONTIER-1 results are expected by spring of 2024.ConclusionsWe show that blocking the IL-33 pathway may mitigate glomerular endothelial inflammation in DKD. The findings from the FRONTIER-1 study will provide valuable insights into the therapeutic potential of IL-33 inhibition in DKD.